ABSTRACT Dental caries is the most common chronic disease for humans from ages 6 - 19 years. Untreated caries resultinpulpalseverepathologiesandeventuallyintoothlossbecausedentalenamelcannotregenerate. Although enamel mineral structure is known and several genes have been identified to be involved in the formation of the enamel, yet researchers have not developed cell- and/or gene-based therapies towards reconstruction, regeneration of enamel tissues, prevention and treatment of dental caries. Thus, the need exists to better understand the molecular pathways involved in the development and pathophysiology of enamel structure that could further our knowledge in developing molecular-based approaches to prevent, delayorrepairdamagetodentalenamelhardtissuesfromcaries. Transcription factors play important role during ameloblast fate determination and normal enamel deposition. We reported that the Msx2 transcription factor when mutated in mice leads to an enamelphenotype.TheMsx2mutantameloblastsreachthesecretorystageoftheirdifferentiationprocess but they deposit sparse amounts of enamel matrix (Bei et al., 2004). Our current preliminary studies indicate that a member of the NKX family of homeodomain transcription factors, the Nkx2.3, is also important for amelogenesis. The Nkx2.3 knockout mice exhibit an amelogenesis phenotype similar to that ofMsx2mutantmice.Inaddition,theexpressionofthesecretedproteinenamelinisselectivelyreducedin both Msx2 and Nkx2.3 deficient secretory ameloblasts. These observations serve as the basis for our proposed hypothesis, that the molecular function of Msx2 and Nkx2.3 transcription factors during amelogenesis depends on their combinatorial action and they are part of a context dependent, amelogenesis-specific transcription factor network. To address this hypothesis, we will study the developmentalresponseoftoothmorphogenesistoperturbedMsx2andNkx2.3transcriptionalregulations andwewilltestthehypothesisthatduringamelogenesisMsx2exertsitsfunctionthroughinteractionswith transcriptionfactorsthat,likeNkx2.3,areco-expressedwithMsx2inameloblastsandwillcharacterizethe Msx2-interacting partners in vitro and in vivo. Understanding how regulatory proteins function in concert with other genes to regulate amelogenesis is fundamental to dental health. If successful, this project will leadto better understandingof themechanisms controlling dental enameltissues formation and will result in opportunities to develop better treatment options for caries and other dental enamel diseases, such as amelogenesisimperfectathatimpactdentalhardtissuehealth.